Targeted metabolomics revealed changes in phospholipids during the development of neuroinflammation in Abcd1 tm1Kds mice and X‐linked adrenoleukodystrophy patients (original) (raw)
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Biochemical Medicine and Metabolic Biology, 1991
Adrenoleukodystrophy (ALD) is an X-linked disorder characterized by demyelination and adrenal insufficiency (I). The disease has a broad spectrum of clinical severity. Patients with the childhood form of ALD typically show rapidly progressive central nervous system demyelination and die several years after onset. Patients with a more chronic variant form of ALD, adrenomyeloneuropathy (AMN), usually develop symptoms related to peripheral neuropathy and myelopathy in the second or third decade of life, with slow progression over many years. Patients with either clinical form of X-linked ALD accumulate saturated verylong-chain fatty acids (VLFA) with carbon length greater than C22 in various tissues, including cultured skin fibroblasts (2,3). The primary biochemical defect in ALD is impaired VLFA oxidation (4-7) due to deficiency of peroxisomal lignoceroyl-CoA synthetase (ligase) (8-11). VLFA oxidation occurs chiefly in peroxisomes (12,13), and patients with Zellweger syndrome, who lack recognizable peroxisomes (14,15), also have impaired VLFA oxidation and accumulate these fatty acids (12,16,17). The basis for phenotypic variability in ALD is unknown. In some kindreds with X-linked ALD, both childhood ALD and AMN have been observed (1,18,19), suggesting that factors other than the primary mutation in the ALD gene may influence the clinical expression of this disease. It is unclear, however, whether alterations in VLFA or lipid metabolism may be responsible for this phenotypic variation. In other inherited lipidoses, including Niemann-Pick disease (20), GM2 gangliosidosis (21), Krabbe disease (22), and metachromatic leukodystrophy (22), studies with cultured fibroblasts have demonstrated a correlation between the extent of biochemical abnormality and the clinical phenotype. A detailed comparison of the biochemical defect in ALD patients with severe symptoms and mild disease has not been reported. To determine whether biochemical differences underlie phenotypic variation in X-linked ALD, we have 74
Plasma phospholipid fatty acids in X-linked adrenoleukodystrophy
Clinical Chemistry, 1996
Blood cell and plasma lipid classes and their fatty acids were analyzed in a child with X-linked adrenoleukodystrophy. The increase in saturated fatty acids with very long chains typical of this disease occurred almost exclusively in sphingomyelin. In this lipid, the proportion of lignoceric (24:0) and hexacosanoic (26:0) acids increased while that of 18:0, 20:0, and 24:1 decreased. In the rest of the lipid classes, but especially in cholesteryl esters and triacylglycerols, the proportion of linoleate (18:2) decreased while that of oleate (18:1) increased. In glycerophospholipids, polyunsaturated fatty acids such as 20:4n-6, 22:5n-6, and 22:6n-3 were reduced while their immediate precursors, 20:3n-6, 22:4n-6, and 22:5n-3, respectively, were relatively increased, suggesting a defect in fatty acid desaturation mechanisms. Although less pronounced, a similar trend of changes was seen in the patient's mother; in both, all alterations were more marked in serum than in blood cells.
Molecular genetics and metabolism, 2007
X-linked adrenoleukodystrophy (X-ALD) is a fatal neurodegenerative disease caused by mutations in the ABCD1 gene, encoding a member of the peroxisomal ABC transporter family. The ABCD1 protein transports CoA-activated very long-chain fatty acids (VLCFAs) into peroxisomes for degradation via b-oxidation. In the severest form, X-ALD patients suffer from inflammatory demyelination of the brain. As the extent of the metabolic defect in the main immune cells is unknown, we explored their phenotypes concerning mRNA expression pattern of the three peroxisomal ABC transporters, VLCFA accumulation and peroxisomal b-oxidation. In controls, ABCD1 expression was high in monocytes, intermediate in B cells and low in T cells; ABCD2 expression was extremely low in monocytes, intermediate in B cells and highest in T cells; ABCD3 mRNA was equally distributed. In X-ALD patients, the expression patterns remained unaltered; accordingly, monocytes, which lack compensatory VLCFA transport by ABCD2, displayed the severest biochemical phenotype with a 6-fold accumulation of C26:0 and a striking 70% reduction in peroxisomal b-oxidation activity. In contrast, VLCFA metabolism was close to control values in B cells and T cells, supporting the hypothesis that sufficient ABCD2 is present to compensate for ABCD1 deficiency. Thus, the vulnerability of the main immune cell types is highly variable in X-ALD. Based on these results, we propose that in X-ALD the halt of inflammation after allogeneic hematopoietic stem cell transplantation relies particularly on the replacement of the monocyte lineage. Additionally, these findings support the concept that ABCD2 is a target for pharmacological induction as an alternative therapeutic strategy.
Indian Journal of Clinical Biochemistry, 2007
X-linked adrenoleukodistrophy is a severe neurodegenerative disorder with impaired very long chain fatty acid metabolism. The disease associated ABCD1 gene encodes a peroxisomal membrane protein which belongs to the superfamily of ATP-binding cassette transporters. We investigated eight male X-ALD patients diagnosed among 142 suspected patients referred for investigation. Plasma levels of very long chain fatty acids were measured at our laboratory using capillary gas chromatography. Eight cases of childhood X-ALD were diagnosed. This is the first published series of Serbian patients with X-ALD. In addition, diagnosis identifies carriers, which could be benefit for genetic counselling and prenatal diagnosis.
Inflammatory profile in X-linked adrenoleukodystrophy patients: Understanding disease progression
Journal of cellular biochemistry, 2017
X-linked adrenoleukodystrophy (X-ALD) is an inherited disease characterized by progressive inflammatory demyelization in the brain, adrenal insufficiency and an abnormal accumulation of very long chain fatty acids (VLCFA) in tissue and body fluids. Considering that inflammation might be involved in pathophysiology of X-ALD, we aimed to investigate pro and anti-inflammatory cytokines in plasma from three different male phenotypes (CCER, AMN and asymptomatic individuals). Our results showed that asymptomatic patients presented increased levels of pro-inflammatory cytokines IL-1β, IL-2, IL-8 and TNF-α and the last one was also higher in AMN phenotype. Besides, asymptomatic patients presented higher levels of anti-inflammatory cytokines IL-4 and IL-10. AMN patients presented higher levels of IL-2, IL-5 and IL-4. We might hypothesize that inflammation in X-ALD is related to plasmatic VLCFA concentration, since there were positive correlations between C26:0 plasmatic levels and pro-inflam...
Molecular Genetics and Metabolism, 2000
X-linked adrenoleukodystrophy (X-ALD) is a progressive demyelinating disorder whose neurological signs and symptoms can manifest in childhood as cerebral ALD or in adulthood in the form of a progressive myelopathy (AMN). The consistent metabolic abnormality in all forms of X-ALD is an inherited defect in the peroxisomal -oxidation of very long chain (VLC) fatty acids (>C 22:0 ) which may in turn lead to a neuroinflammatory process associated with demyelination of the cerebral white matter. The current treatment for X-ALD with Lorenzo's oil aims to lower the excessive quantities of VLC fatty acids that accumulate in the patients' plasma and tissues, but does not directly address the inflammatory process in X-ALD. We have previously demonstrated that lovastatin and other 3-HMG-CoA reductase inhibitors are capable of normalizing VLC fatty acid levels in primary skin fibroblasts derived from X-ALD patients. Lovastatin can block the induction of inducible nitric oxide synthase and proinflammatory cytokines in astrocytes, microglia, and macrophages in vitro. In a preliminary report, we demonstrated that lovastatin therapy can normalize VLC fatty acids in the plasma of patients with X-ALD. Here we report our clinical and biochemical observations on 12 patients with X-ALD who were treated with lovastatin for up to 12 months. Our results show that the high plasma levels of hexacosanoic acid (C 26:0 ) showed a decline from pretreatment values within 1 to 3 months of starting therapy with 40 mg of lovastatin per day and stabilized at various levels during a period of observation up to 12 months. The percentage decline from pretreatment values varied and did not correlate with the type of ALD gene mutation (point mutation versus gene deletion). In 6 patients, in whom red cell membrane fatty acid composition was studied, a mean cor-rection of 50% of the excess C 26:0 was observed after 6 months of therapy suggesting sustained benefit. In a few patients who discontinued lovastatin therapy plasma C 26:0 levels reverted to pretreatment values suggesting a cause and effect relationship between these events. Two patients dropped out of the study claiming no clinical benefit, 1 was withdrawn due to adverse effects, and an adult patient with cerebral involvement died during the study. A 10-year-old boy with severe cerebral involvement showed worsening of his neurological status. All patients with AMN remained neurologically stable or showed modest subjective improvement. All patients who did not have Addison's disease at the time of enrollment maintained normal adrenal function throughout the study. The implications of our findings for developing an effective therapy for X-ALD are discussed.
X-linked adrenoleukodystrophy phenotype is independent of ABCD2 genotype
Biochemical and Biophysical Research Communications, 2008
Strikingly variable clinical phenotypes can be found in X-linked adrenoleukodystrophy (X-ALD) even with the same ABCD1 mutation. ABCD2 is the closest homolog to ABCD1. Since ABCD2 overexpression complements the loss of ABCD1 in vivo and in vitro, we have investigated the possible role of the ABCD2 gene locus as determinant of X-ALD phenotypes. Sequence and segregation analysis of the ABCD2 gene, in a large X-ALD family with different phenotypes disclosed that the identical ABCD2 alleles were inherited in brothers affected by mild (noncerebral) versus severe (childhood cerebral) X-ALD phenotypes. Moreover, two independent association studies of ABCD2 polymorphisms and clinical phenotypes showed an even allele distribution in different X-ALD phenotypes and controls. Based on these findings ABCD2 can be excluded as a major modifier locus for clinical diversity in X-ALD. These findings are of particular importance for the attempt of pharmacological induction of ABCD2 as a possible therapeutic approach in X-ALD.
PLoS ONE, 2011
X-linked adrenoleukodystrophy (X-ALD) affects the nervous system white matter and adrenal cortex secondary to mutations in the ABCD1 gene that encode the peroxisomal membrane protein. We conducted a genomic and protein expression study of susceptibility gene with its clinical and biochemical analysis. To the best of our knowledge this is the first preliminary comprehensive study in Indian population that identified novel mutations and SNPs in a relatively large group. We screened 17 Indian indigenous X-linked adrenoleukodystrophy cases and 70 controls for mutations and SNPs in the exonic regions (including flanking regions) of ABCD1 gene by direct sequencing with ABI automated sequencer along with Western blot analysis of its endogenous protein, ALDP, levels in peripheral blood mononuclear cells. Single germ line mutation was identified in each index case in ABCD1 gene. We detected 4 novel mutations (2 missense and 2 deletion/insertion) and 3 novel single nucleotide polymorphisms. We observed a variable protein expression in different patients. These findings were further extended to biochemical and clinical observations as it occurs with great clinical expression variability. This is the first major study in this population that presents a different molecular genetic spectrum as compared to Caucasian population due to geographical distributions of ethnicity of patients. It enhances our knowledge of the causative mutations of X-ALD that grants holistic base to develop effective medicine against X-ALD.